CN1174546A - Solventless process for making 2, 6 -difluorobenzonitrile - Google Patents
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Abstract
A process for making 2,6-difluorobenzonitrile, comprising reacting 2,6-dichlorobenzonitrile with a substantially anhydrous metal fluoride at a temperature between about 160 DEG C. and about 300 DEG C. and in the presence of a phase transfer catalyst, which is typically a polyether, tetra-substituted phosphonium salt, tetra-substituted ammonium salt, and cryptand, but in the absence of a solvent. After taking off the product the resulting mixture may be recycled into the reactor for the next reaction cycle. Upon build-up of tars in the reaction process, the invention includes the separation of catalyst from the tars and the recycle thereof.
Description
Field of the present invention
The present invention relates to by 2,6-dichloro-benzonitrile and anhydrous metal fluoride basically are in the presence of solvent-free but reaction production 2 in the presence of phase-transfer catalyst, and the method for 6-difluoro benzonitrile relates to wherein catalyst recovery and round-robin method.
Background of the present invention
2,6-difluoro benzonitrile particularly is a kind of useful as intermediates in the agrochemical industry in various industry.The method of existing a large amount of these intermediates of preparation.The UK2142018B of Ishihara Sangyo Kaisha Limited discloses 2, and 6-dichloro-benzonitrile and Potassium monofluoride are depressed reaction at 200 to 450 ℃ with adding in the presence of solvent-free.More specifically, the patent disclosure of Ishihara use 21.5kg/cm at least
2Pressure.Except not using the solvent, the Ishihara disclosed method is not used catalyzer.The open #87-114 of the Japanese Patent of Sumitomo Chem.Industries, 939 (Derwent publication #87-183186126) disclose benzonitrile and alkaline metal fluoride cpd and alkaline-earth metal fluoride and have reacted down for 100 to 250 ℃ in temperature in the presence of solvent-free.
The Japanese Patent 90-004 of Dainippon Ink Chemical, 580 (Derwent publication #83-05838k/03) disclose the method by mixture and the crown ether catalyzer and the parachloronitrobenzene prepared in reaction p-fluoronitrobenzene of KF and alkaline metal fluoride cpd (except the KF) or alkaline-earth metal fluoride.The open No.89-1013 of the Japanese Patent of Ihara Chemical Industries, 037 (Derwent publication #89-059218/08) disclose by alkaline metal fluoride cpd and have adopted catalyst mixture to prepare halogenated aromatic compound.Catalyst mixture comprises quaternary ammonium salt and/or quaternary alkylphosphonium salt and crown ether and/or polyalkylene glycol.
The US4 of Bayer Akt iengesellschaft, 226,811 require a kind of method by replacement chlorobenzene and Potassium monofluoride prepared in reaction fluorinating aromatic ring compounds in the presence of crown ether catalyzer and solvent.The US 4 of Bayer Aktiengesellschaft, 978, as 2, the nucleophilic exchange between 6-difluoro benzonitrile and the KF prepares the method for aromatics fluorochemical by raw material in the presence of the metal-salt of phase-transfer catalyst and the periodic table of elements the 3rd to 5 main group and subgroup element in 769 requirements.The example of these salt comprises chromic salts (CrCl
3* 6H
2O), molysite (FeCl
3), cobalt salt (CoCl
2* 6H
2O), zinc salt (ZnCl
2) and antimonic salt (SbCl
3).
The US 3,300,537 of Bennett (transferring The National Smelting Company) discloses the method that the halogenated aromatic rings that will not contain activating group such as nitro is converted into fluorinated aromatic compounds.This reaction is carried out under high pressure not using under solvent or the catalyzer under 300 to 700 ℃ of high reaction conditionss with dry alkaline metal fluoride cpd.
Consider preceding method, need have especially produce high yield, to environmental optimization and economic method.A problem using the crown ether catalyzer as mentioned above is that they are expensive especially, therefore makes that these methods are uneconomical for industrial production.
The present invention's general introduction
The present invention relates to prepare 2, the method for 6-difluoro benzonitrile (hereinafter referred to as DFBN).DFBN is by 2,6-dichloro-benzonitrile (hereinafter referred to as DCBN) and anhydrous basically metal fluoride temperature about 160 ℃ to about 300 ℃ of following prepared in reaction.Be reflected under the phase-transfer catalyst existence and carry out.Phase-transfer catalyst is generally polyethers, four Qu Dai phosphonium salts, four substituted ammonium salts or cryptand.
The anhydrous metal fluorochemical can be by the combination preparation with reaction mixture component distillation, oven dry at high temperature, spraying drying or these technology under vacuum.Dry metal fluoride is favourable in the presence of solvent-free, because solvent is tending towards moisture absorption and is difficult to drying.Another advantage of not using solvent is not need to carry out product/separated from solvent.Metal fluoride can be Sodium Fluoride, cesium fluoride, Potassium monofluoride, rubidium fluoride or cuprous fluoride.Potassium monofluoride is preferred.Polyethers is preferably used as catalyzer, and crown ether is most preferred polyethers.
An intermediate of reaction is a 2-chloro-6-fluorine benzonitrile (hereinafter referred to as CFBN).CFBN can be recycled in the subsequent reactions as an ongoing production method part.The conversion of DCBN to DFBN not only generates CFBN as intermediate, and has unreacted DCBN and tar (being diaryl ether) in the gained mixture of reaction products.
After finishing the halogenide permutoid reaction, can be by filtration or more preferably by water extracting and separating unreacted metal fluoride salt and metal chloride salt.Then from organic phase decantation gained metal fluoride/metal chloride salt solution and can with its by stripping apparatus to reclaim the volatile organic matter of any remnants.DFBN in the product mixture can separate from reaction product mixture by using vacuum distillation technique.Take out required DFBN from reaction product mixture after, the mixture that gained can be contained CFBN, unreacted DCBN, catalyzer, tar and any remaining DFBN is recirculated into reactor (second kind of mixture).Can repeat entire method if need.
DCBN, CFBN can be separated with any residue DFBN and circulate and comprise the third mixture of tar and catalyzer with production.According to the performance and the value of catalyst system therefor, can filter the insoluble catalyst recovery catalyzer of gained then by mixture being added solvent as in alcohol, organic aromatic hydrocarbons or the nitrile solvent.Other isolation technique also can be used for reclaiming some catalyzer, as stripping and distillation.Detailed description of the present invention
The present invention relates to prepare 2, the method for 6-difluoro benzonitrile (hereinafter referred to as DFBN).According to the present invention, DFBN passes through 2,6-dichloro-benzonitrile (hereinafter referred to as DCBN) and anhydrous basically metal fluoride prepared in reaction.Usually, this halogen exchange reaction carries out under about environmental stress under about 160 ℃ to about 300 ℃ of temperature.Be reflected under the phase-transfer catalyst existence and carry out.Phase-transfer catalyst used herein is meant the catalyzer that increases the concentration of fluorochemical in organic phase.Phase-transfer catalyst is selected from polyethers, four Qu Dai phosphonium salts, four substituted ammonium salts and cryptand usually.Polyethers is generally crown ether or linear polyether.
The anhydrous metal fluorochemical can be by about 110 ℃ of following component distillation reaction mixture preparations in a vacuum.Other technology can be used for dry metal fluoride as the combination of oven dry at high temperature or spraying drying or these technology in a vacuum.Metal fluoride should be dried to mixture and contain the water that is lower than 0.1wt%,, most preferably be lower than the degree of the water of 0.01wt% more preferably less than 0.05%.Metal fluoride can be Sodium Fluoride, cesium fluoride, Potassium monofluoride, rubidium fluoride or cuprous fluoride, and Potassium monofluoride is preferred.
The preferred polyethers that uses is as catalyzer, and crown ether is most preferred polyethers.18-hat-6 ethers are preferred crown ethers.Dibenzo-18-hat-6 crown ethers are that most preferred 18-hat-6 ethers (can be available from ParishChemical of Orem.Utah.)。Other 18-hat-6 ethers and other polymer support or non-carrier polyethers be useful as catalysts also.Ammonium salt can comprise muriate or bromide salt.Ammonium salt is generally the phenyl trimethyl ammonium chloride, the tetraphenylphosphonibromide bromide ammonium, Aliquat 336 (being called the hot ammonium of 1-again): N-methyl-N, N-dioctyl (dioctil)-muriate or tri-n-octyl methyl ammonium chloride, Trimethyllaurylammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, or Arquad 16/60 (being called cetyl trimethylammonium bromide again).Phosphonium salt can be muriate or bromide salt.Shi Yong De phosphonium salt is generally 1-menaphthyl triphenyl phosphonium chloride, methoxymethyl triphenyl phosphonium chloride, 4-nitrobenzyl triphenyl phosphonium chloride and tetraphenyl phosphonium chloride.Can also use cryptand with 6-heteroatoms hat (ether) system.
For forming DFBN, will about 1mol DCBN and about 1 to about 3mol normal metal fluoride and about 0.001 to about 0.5mol normal catalyst reaction.With 1mol DCBN more preferably with about 1.5 to about 2.5mol normal metal fluorides and about 0.01 to about 0.1mol normal catalyst reaction.With 1mol DCBN more preferably with about 1.8 to about 2.2mol normal metal fluorides and about 0.01 to about 0.06 mol normal catalyst reaction.
Reaction more preferably 190 ℃ to about 260 ℃, is most preferably from about carried out under 225 ℃ usually at about 160 to about 300 ℃.Ammonium salt is with the comparatively high temps that phosphonium salt is here discussed is unstable down.Therefore, when using these salt as catalyzer, temperature of reaction is not higher than about 180 ℃ usually; Yet can see in an embodiment, can use comparatively high temps.Reaction times is generally about 1 to about 30 hours, preferred about 10 to about 24 hours.Reaction is carried out under about environmental stress usually, although if necessity also can be used higher pressure.The boiling point of reaction mixture is generally about 200 ℃ to about 235 ℃, but can carry out and reduce with reaction.Therefore, when carrying out under the disclosed comparatively high temps here, reaction can be carried out being higher than under the environmental stress.If be reflected in the closed reactor and carry out, then this is actual especially.
In reaction, produce intermediate 2-chlorine 6-fluorine benzonitrile.The reaction yield of DFBN and CFBN is based on the DCBN of consumption, and this yield is about 90 to about 100%, and usually about 95 to about 98%.CFBN and any remaining DFBN can be recycled in the subsequent reactions as an ongoing production method part.The conversion of DCBN to DFBN not only generates CFBN as intermediate, and has unreacted DCBN and tar (being diaryl ether) in the gained mixture of reaction products.
For dry metal fluoride, except technology discussed above, another selection is catalyzer, DCBN, metal fluoride and the benzonitrile compound that is selected from DFBN, CFBN and its mixture to be sneaked in the reactor and slowly heated this mixture it is refluxed under vacuum.Temperature is not higher than 130 ℃ usually under vacuum.Though the time of heated mixt is unimportant, usually with mixture heating up about 0.1 to about 24 hours, preferred about 1 to about 10 hours.Keep approximately half an hour to about 24 hours temperature, preferred about 1 to about 10 hours, distill out whole DFBN of being present in the reactor and/or about 75wt% of CFBN simultaneously.Usually at the alap pressure of reality, under about 20mmHg absolute pressure, steam benzonitrile compound usually with vacuum distilling.After the drying operation, the temperature of gained mixture rises to about 160 to about 300 ℃, so that by the above-mentioned halogen exchange reaction that carries out.In addition, can after metal fluoride is pressed the preceding method drying, catalyzer and DCBN be added in the reactor.
Reaction product mixture can be removed by filter unreacted metal fluoride salt and any other byproduct salt.Reaction mixture is preferably washed with water to remove these salt.This water-washing step carries out under about 70 ℃ usually, although also can use about 35 to about 100 ℃ temperature.Then metal fluoride/metal chloride salt solution decantation from organic phase being come out also can be by stripping apparatus to reclaim any remaining volatile organic compounds.
For prevent that the metal fluoride of carrying secretly from causing further forming tar in the product removal process, at the preferred salt of carrying secretly in the organic phase that further reduces in above-mentioned washing operation back.The salt of carrying secretly can be removed by washing for the second time.The preferred method that reduces the salt of carrying secretly in the organic phase is to use 2 terrace works, is about to washed reaction product and carries out counter-current extraction and be lower than about 0.5wt% so that the salts contg in the organic phase is limited in.Another benefit that reduces salts contg is the corrosion that reduces to greatest extent various stainless steel equipments used among the preparation method.
Then, can use vacuum distilling technology with DFBN from wash or unwashed product mixture separate.Equally, pressure is remained in actual alap pressure, usually under about 20mmHg absolute pressure.This vacuum was kept about 1 to 12 hour about 8 hours usually.During this period temperature is maintained at about 150 ℃ to about 90 ℃, about 110 times usually; Yet if reaction product is not washed, temperature can be up to 230 ℃.Behind the DFBN that steams aequum from reaction product mixture, the mixture that gained can be contained CFBN, unreacted DCBN, remaining DFBN, catalyzer and tar is recycled in the reactor.This circulation can repeat till needs are removed tar.
Because preferred catalyzer costliness, therefore when using these materials, it is preferred using catalyst recovery system.At least regularly it also is preferred removing tar from reactor, because they are accumulated in time.Therefore the present invention includes and from reaction product mixture, separate DFBN and generate the second kind of mixture that comprises CFBN, unreacted DCBN, catalyzer and come self-reacting tar thus, from second kind of mixture, separate DCBN and CFBN and generate and comprise the third mixture of tar and catalyzer and DCBN and the CFBN that separates is recycled in the reactor.
Usually from second kind of mixture, separate DCBN and CFBN with vacuum or vapor distillation (stripping) technology.Vacuum distilling is preferred for this separation.Because the distillation efficiency of DCBN is low, therefore before beginning to remove tar and recycling catalyst operation, need DCBN is reacted completely as far as possible.If use vapor distillation, then gained water decantation from the gained organic phase is come out, then can be before discharging by the active-carbon bed any organism that residues in aqueous phase of removing.When using vapor distillation, there is minimum ebullient heterogeneous azeotrope, its allows to carry out vapor distillation usually under about normal atmosphere and about 100 ℃.After using the stripping operation, the organic phase that is in the stripping container bottom is difficult to come out from the aqueous phase decantation, and reason is that organic phase has usually very near about 100 ℃ zero pour.Can optionally the viscosity of organic phase be reduced with efficient solubility promoter such as xenyl phenyl ether (hereinafter referred to as BIPPE).Use solubility promoter that the decantation operation is more easily carried out.
The second method that reclaims unreacted DCBN and CFBN from tar and catalyzer is to carry out vacuum distilling in the solubility promoter existence or not.Use vacuum distilling but not steam distilled key advantage is to avoid colder ground decantation viscous liquid or semi-solid state organic phase from water.Main drawback is unless use solubility promoter, to generate the very organic phase of small volume when vacuum distilling finishes.In carrying out vacuum distilling, use can be higher than 235 ℃ of small volume reboilers of operation down in temperature usually.Vacuum distilling at about 250 ℃ and actual alap pressure, is carried out under about 20mmHg absolute pressure usually usually.If there is relatively large DCBN, can use reheater condenser; In addition, can be enough to prevent that greater than about 65 ℃ of condensers of operating down CFBN from solidifying in temperature.For preventing that DCBN and CFBN from falling into that vacuum distillation plant preferably includes post backwater leg (column drainback leg) or trap in the tar.
According to the performance of the catalyzer of selecting with the economic worth of its recovery, reclaim technology and comprise stripping, extraction, distillation and filter method.Can then distill from the third mixture that contains tar (and solubility promoter (if use)) by stripping and reclaim catalyzer.Preferred technology is that tar and solubility promoter are dissolved in the suitable solvent neutralization by the insoluble catalyzer of filtered and recycled.Because in fact some An Huo Phosphonium catalyzer has been bought easily and is inexpensive, therefore needn't from the mixture of catalyzer and tar, reclaim catalyzer, and normally that this mixture is discarded.
Tar dissolves in alcohol, organic aromatic hydrocarbons or nitrile solvent such as methyl alcohol, acetone, acetonitrile, toluene and the chlorobenzene.Solvent is preferably methyl alcohol.Can use solvent and tar weight ratio about 5: 1 to about 20: 1, operating weight was than about 10: 1 usually.The tar extraction step can be carried out to the temperature of boiling point in the zero pour of solvent, although the tar extraction step also can be carried out under 20 ℃ in moderate temperature usually according to appointment.
Dissolution with solvents tar and solubility promoter, but catalyzer is precipitated out from solvent.Available then known filter method reclaims catalyzer.These technologies can include but not limited to centrifugal and pressurization or vacuum filtration.Suitable filter plant comprises piped, level or vertical leaf filter or have the about 25ft of volume
3And the suction filter type filter of filter cake (throw out of recovery) washability.Usually with the catalyzer organic solvent and the water washing of reclaiming, drying is recycled in the reactor then.If need, can then the dissolved catalyst stream be recycled in the reactor by the catalyzer that from strainer, reclaims in the hot-fluid (for example at least about 60 ℃) that catalyzer is dissolved in DFBN, DCBN, CFBN or its mixture.Solvent is dissolved tar not only, and play reduction will be by the effect of the thinner of fluoride concn in the stream of depleted tar suitably.
EXAMPLE Example 1-A part: fluoridize DCBN with KF
(d=1.40) the dry KF of DFBN, 203g (3.5mol) and 285g (1.66mol) DCBN drop in the 1000mL 4-neck round-bottomed flask and with material and heat with 230g (165mL).This flask is loaded onto condenser, mechanical stirrer and thermowell.Condenser is installed between reactor (flask) and the source nitrogen.Because KF adds among DFBN and the DCBN, reaction mixture becomes and can not reach 140 ℃ until temperature by whipped state.Still is heated to 150 ℃.During the reaction beginning, the concentration of DCBN is 55.3wt%.The concentration of DFBN is 44.7wt%.The sign that reaction is carried out does not appear, because the concentration of DCBN did not change in 1.5 hours.At this moment, add the amino phase-transfer catalyst of 3g three (two oxa-s 3,6-heptyl).With still temperature rise to 170 ℃.React after 24 hours, the concentration of DCBN is 45wt%, and the concentration of CFBN is 8wt%, and the DFBN product concentration is 45wt%.React after 48 hours, the concentration of DCBN is 40wt%, and the concentration of CFBN is 13wt%, and the DFBN product concentration is 48.7wt%.Add 2g 18-hat-6 catalyzer.React after 72 hours, the concentration of DCBN is 18wt%, and the concentration of CFBN is 27wt%, and the DFBN product concentration is 51wt%.Because reaction is carried out slowly, add 2.8g 18-hat-6 catalyzer again.When 96 hours reaction times, the concentration of DCBN is 1wt%, and the concentration of CFBN is 16wt%, and the DFBN product concentration is 80wt%.When 120 hours reaction times, initial substance is reacted, and the concentration of CFBN is 7wt%, and the DFBN product concentration is 89wt%.When 146 hours reaction times, the concentration of CFBN is 3wt%, and the DFBN product concentration is 93wt%.When 146 hours reaction times, the concentration of CFBN is 3wt%, and the DFBN product concentration is 93wt%.When 150 hours reaction times, the concentration of CFBN is 2wt%, and the DFBN product concentration is 97wt%.Reaction mixture is cooled to 55 ℃, adds 1100mL water, mixture is separated.The concentration of gained salts solution (salt solution) is 14wt%.Washed product is 457.5g 96.4 wt%DFBN, is 460g based on DCBN initial substance that adds and the calculating output of DFBN, and yield is 95.8%.B part: vapor distillation DFBN product
To drop in 1 liter of 4-neck round-bottomed flask from most products (453g 96.4wt%DFBN) of A part.Flask is loaded onto short Vigreux column, condenser, reception vapour pipe and thermowell.Receptor is cooled off in ice/water-bath.The vapor distillation of DFBN carried out 4 hours and identified possible product loss (if this method step is included in the order but not stage of cutting apart).The DFBN distillate is separated from water, melted and be collected in the brown sample bottle.Distillate weighs 403g and comprises the DFBN of 98.4wt%.Based on the calculating output that adds the DFBN initial substance in the distiller is 430g, and yield is 93.6%.The water that cat head distills out is 1925g, and the water that remaines in the distiller is 117g.Being used for steam distilled Total Water is 2042g.Distiller contains on a small quantity not cat head distilled (16g) DFBN.From solidify DFBN product bottle, isolate the eutectic mixture of a small amount of (17g) 80wt%DFBN and 16wt%CFBN.Embodiment 2-fluoridizes DCBN with KF
(3.32mol) DFBN and 285g (1.66mol) DCBN drop into and have in the cylindrical flask of 1000mL 4-neck (Monel 400) of 4 Internal baffles with 462g (330mL).This flask is loaded onto two condensers, had mechanical stirrer and the thermowell of two accumulation agitators (stacked agitator).A condenser is installed between reactor (flask) and the nitrogen inlet mouth.Add 205g (3.5mol) KF after still is heated to 170 ℃.Temperature regulator is set at 170 ℃ and add 4g 18-hat-6 catalyzer (0.5wt% is by the weight of DFBN and reactant).When the reaction beginning, the concentration of DCBN is about 38.3wt%.React after 4 hours, the concentration of DCBN is 23.3wt%, and the concentration of CFBN is 12.3wt%, and the DFBN product concentration is 60.wt%.Stirring velocity is set at 300rpm.React after 18 hours, the concentration of DCBN is 5.5wt%, and the concentration of CFBN is 18.2wt%, and the DFBN product concentration is 74.7wt%.Stirring velocity is risen to 400rpm.When 24 hours reaction times, the concentration of DCBN is 3.3wt%, and the concentration of CFBN is 16wt%, and the DFBN product concentration is 78.3wt%.When 40 hours reaction times, the concentration of DCBN is 1.4wt%, and the concentration of CFBN is 14wt%, and the DFBN product concentration is 82wt%.Motor stirring velocity risen to 1000rpm reduces to 600rpm then, because can not keep higher speed.When 48 hours reaction times, the concentration of CFBN is 3wt%, and the DFBN product concentration is 93wt%, adds 3.6g 18-hat-6 catalyzer again, and making total catalyst is 7.6g (1.02wt% is by the weight sum of DFBN and reactant).When 64 hours reaction times, the concentration of CFBN is 1.4wt%, and the DFBN product concentration is 98wt%.Reaction product mixture is cooled to 35 ℃ spends the night.
Second day, carry out vapor distillation by the description of embodiment 1.All organism (DFBN) can be thought and distill from cat head in 2.5 hours.The KCl/KF salts solution (salt solution) that obtains from reactor is painted by the brown throw out.The salt concn that calculates is 30wt%.The DFBN overhead product is separated from the water distillate, melted and be collected in the brown sample bottle.The weight of DFBN overhead product is 630.5g, and purity is 98.4%.The heavy 2592g of the water that cat head distills out.The DFBN gross weight that reclaims is 626.7g (4.5mol), and the CFBN gross weight of recovery is 10.2g (0.07mol), and the yield of DFBN and CFBN is 93% of a theoretical yield.Embodiment 3: fluoridize DCBN with KF
(330mL) DFBN and 285g (1.66mol) DCBN drop into and have in the cylindrical flask of 1000mL 4-neck (Monel 400) of 4 Internal baffles with 462g (3.32mol).This flask is loaded onto two condensers, the mechanical stirrer that has two accumulation agitators and thermowell.A condenser is installed between reactor (flask) and the nitrogen inlet mouth.Temperature regulator is set at 150 ℃.When temperature reaches 150 ℃, 205g (3.5mo1) KF is added in the reaction mixture.With reaction mixture with high-speed grinder (18,000rpm) grind 2 minutes to reduce KF crystalline size.After the grinding, add 10g 18-hat-6 catalyzer (1.0mol% is by KF).During the reaction beginning, the concentration of DCBN is about 38.3wt%.React after 2 hours, the concentration of DCBN is 30.9wt%, and the concentration of CFBN is 4.8wt%, and the DFBN product concentration is 63.1wt%, and stirring velocity is set at 500rpm.React after 18 hours, initial substance is 14wt%, and the concentration of CFBN is 14wt%, and the DFBN product concentration is 71.1wt%, and stirring velocity is set at 400rpm.When 24 hours reaction times, the concentration of DCBN is 7.1wt%, and the concentration of CFBN is 17wt%, and the DFBN product concentration is 75wt%.When 40 hours reaction times, the concentration of DCBN is 1.4wt%, and the concentration of CFBN is 9.7wt%, and the DFBN product concentration is 87.8wt%.Motor stirring velocity risen to 1000rpm reduces to 500rpm then, because can not keep higher speed.When 48 hours reaction times, the concentration of CFBN is 12wt%, and the DFBN product concentration is 84.5wt% and adds 2g 18-hat-6 catalyzer.When 64 hours reaction times, the concentration of CFBN is 8.4wt%, and the DFBN product concentration is 90.3wt%.When 72 hours reaction times, the concentration of CFBN is 6.9wt%, and the DFBN product concentration is 91wt%.When 88 hours reaction times, the concentration of CFBN is 4.5wt%, and the DFBN product concentration is 94wt%.When 96 hours reaction times, the concentration of CFBN is 2.5wt%, and the DFBN product concentration is 97.2wt%.When 120 hours reaction times, the concentration of CFBN is 2wt%, and the DFBN product concentration is 98wt%.
Reaction product mixture is cooled to 45 ℃, adds 700mL water, and this mixture is separated.Gained brinish salt concn is 27wt%.Washed organic products is the DFBN (yield 91.3%) of 645g purity 98%.Embodiment 4: preparation
In embodiment 4, use following method and apparatus:
1. the suitable temperature adjustment solution of glycol/water circulation bath pumping solidifies to avoid material by still head, condenser and overhead product susceptor.
2. the overhead stirrer system (overhead stirrer system) that is used for glassware comprises polished glass agitator handle and Ace TRUBORE Teflon agitator bearing (comprising Teflon neck bearing, nylon sleeve and FETFE " 0 " ring), nylon set nut, Teflon support " 0 " ring and Ace-Thread glass adapter.This equipment need bear the vacuum that is low to moderate 0.1mm and prevent that volatile organic matter from leaking in high-temperature reaction process.
3. provide the stainless steel tube of oven dry to link to each other with the shaking table of use.
4. the experiment tubular reactor system of preheating is provided.
42g DFBN (with melt form) is added in the 250mL three neck round-bottomed flasks of the water distilling apparatus (the vacuum jacket layer 10-tower tray Oldershaw post of jacket layer splitter and overhead product collection device is housed) that overhead stirrer and jacket layer are housed.Material is heated to 60 ℃, adds 141g (0.9mol) CFBN, 86g (0.5mol) DCBN, 8.0g IPN (internal standard substance), 9.1g (0.025mol) dibenzo-18-hat-6-crown ether catalyzer and 65g (1.1mol) KF then.The weight of total mixture is 351.5g before the distillation.Vacuum imposed in the system and with system pressure slowly reduce to≤10 torrs.After setting up required pressure, water acutely steams from system.In case set up required pressure, then with the still temperature rise until solution steadily reflux (temperature≤110 ℃).With system by behind the 10-tower tray Oldershaw column equilibration, open the backflow splitter of setting 5: 1 reflux ratios and in 2-3 hour at overhead collection 36gDFBN.After the distillation, the gross weight of mixture is 316g.Set up normal atmosphere again and reaction mixture temperature is transferred to 100 ℃ with nitrogen.Adopt following technology that mixture is taken a sample then, also divide bleed with Karl Fisher titrator by liquid-phase chromatographic analysis.
Two disposable glass pipets of 15cm (end of a transfer pipet broken and the spile of filter paper is inserted in another transfer pipet) and a 20mL phial are heated to about 60 ℃ with heating gun.Uncracked transfer pipet is put into 20mL phial near reaction unit, and from mixture, take out the 1-2mL sample with the disruptive transfer pipet.Sample is quickly transferred in the uncracked transfer pipet, and transfer pipet, phial and solution are moved in the titrator fast.Promote hot solution with the transfer pipet bead and add Aquastar by filter paper plug and transfer pipet stem and with four (60mg) liquid
TMIn the titrator.
In case after determining the mixture drying, solution temperature is risen to 200 ℃ makes the reaction beginning.In reaction process, mixture becomes light brown again from the light yellow brown that becomes.On the reaction mixture surface, form some KF and KCl salt deposit.To reaction mixture sampling regularly and by liquid phase or gas chromatographic analysis.When reaction finishes, easy stirred mixture is cooled to 100 ℃ and in 1 liter of plastics separatory funnel of going into to be added with in advance 250-500mL water (preheating to 80 ℃).The jolting two-phase mixture two is separated this about 1-3 minute then.The bottom organic layer is separated from upper aqueous layer.Observing little burr layer at the interface and advancing with organic layer.On the brown water layer of remainder, observe a small amount of organic substance pond.After separation is finished, analyze this two-layer organic content.Organic phase contains have an appointment 90g DFBN, 130gCFBN, 20g DCBN, 9g catalyzer, the various diaryl ether impurities of 3g and internal standard substance.Then organic mixture is turned back in the reactor in preparation circulation next time.Embodiment 5 circulation for the second time
To be equipped with in the 250mL three neck round-bottomed flasks of water distilling apparatus (the vacuum jacket layer 10-tower tray Oldershaw post of jacket layer splitter and overhead product collection device is housed) of overhead stirrer and jacket layer from the organic substance input among the front embodiment 4.Material is heated to 60 ℃, then vacuum is imposed in the system and with system pressure slowly reduce to about 10 torrs and by distillation steam a part of DFBN of producing in the reaction of front (73.5g, 0.52mol).But for drop into the also system in the efficient drying preparation of this distillation of DCBN and KF next time.After steaming the DFBN product, with nitrogen remove vacuum and with DCBN (86g, 0.5mol) and KF (65g is 1.1mol) in the adding reactor.The further dehumidification system of CFBN by the remaining DFBN of vacuum distilling and about 1wt%.Heat material 18-24 hour down at 200 ℃ drying back (＜100ppm water is measured by using Karl Fisher titrator).After reaction is finished, desalt to remove by processing reaction product mixture described in the embodiment 4.Organic phase contains the mixture of the 70gDFBN that has an appointment, 120g CFBN, 40gDCBN, 9g catalyzer, three kinds of diaryl ether impurities of 6g and internal standard substance.Embodiment 6: simulate 30 circulations (for tar)
Tar material (20g fluoridizes the mixture with the chlorination diaryl ether) is mixed in the 500mL three neck round-bottomed flasks of the distiller that overhead stirrer and jacket layer are housed (the vacuum jacket layer 10-tower tray Oldershaw post of jacket layer splitter and overhead product collection device is housed) with 200g (1.44mol) DFBN, 56g (0.326mol) DCBN, 41.6g (0.74mol) KF, 8.0g dibenzo-18-hat-6 catalyzer and internal standard substance.After steaming about 50mL DFBN by vacuum distilling, with nitrogen remove vacuum and with mixture 260 ℃ of heating 14 hours down.Then this mixture is cooled to 60 ℃ and to going into 260g water (being preheated to 60 ℃).Carry out that layer separates and product is analyzed.This organic layer contains other 40.5g (0.29mol) DFBN, 49g (0.32mol) CFBN, 0g DCBN, 8.0g dibenzo-18-hat-6 catalyzer and other 2.9g diaryl ether tar.Embodiment 7: use the dibenzo-18-that reclaims from tar removing step to be preced with-6 catalyzer
Dibenzo-the 18-that reclaims is preced with-6 catalyzer (4.85g, 0.01mol) and round-robin organic mixture (28g DFBN, 56g CFBN and 10g DCBN), and other DCBN (46.3g, 0.27mol), KF (33g, 0.57mol) and internal standard substance in the 250mL three neck round-bottomed flasks of the distiller that overhead stirrer and jacket layer are housed (the vacuum jacket layer 10-tower tray Oldershaw post of jacket layer splitter and overhead product collection device is housed), mix.After steaming about 50mLDFBN by vacuum distilling, with nitrogen remove vacuum and with mixture 210-220 ℃ of heating 11 hours down, be cooled to 80 ℃ and described in embodiment 6, wash.Final organic layer contains the 25g that has an appointment (0.18mol) DFBN, 49g (0.32mol) CFBN, 12g (0.07mol) DCBN, 5.3g dibenzo-18-hat-6 catalyzer and 2.7g diaryl ether tar.Embodiment 8: catalyst screening embodiment A part: the equipment that uses in the screening process
Screen several catalyzer with the laboratory tubular reactor system.Be sandwiched in two 16 pipes (1/2 " * 3.125 " with cover) that compress in the aluminium sheet (9.125 " * 10.25 ") with 4 Chromalox electrically heated chucks (two of each plates) heating.Whole device is placed on the jolting platform (Eberback6005 that has explosion-proof motor and 6040 general casees) that is used to stir, and uses the conventional equipment controlled temperature.For this equipment, can in the single load, screen 16 kinds of catalyzer/conditions, greatly facilitate screening process thus.B part: the method for using in the screening process
Three pipes are distributed to the catalyzer of every kind of screening, and required material (DCBN, KF, catalyzer and DFBN) is added in the pipe.15 pipes are placed between the aluminium sheet that compresses and heating 12 hours under predetermined temperature.Extract a pipe out from each group, the pipe with remainder descended reheat 12 hours at second preset temperature (higher) then.Behind this EO, from each is organized, extract second out and manage and will heat 12 hours at last under three preset temperatures of Guan Zaidi (higher) of remainder.Extract the last batch of pipe behind this EO out.Product mixture in each pipe is dissolved in the KF precipitation that makes KCl and remnants in the acetonitrile.Then with liquid phase or gas chromatographic analysis gained acetonitrile solution.C part: catalyst test embodiment in tubular reactor (dry prevention and internal standard substance)
206g DFBN and 64g KF are dropped in clean 500 milliliters, the three neck round-bottomed flasks of the 15-tower tray Oldershaw post that overhead stirrer and band vacuum distilling head are housed.Then under 100 ℃ (10 torrs) cat head with 5: 1 reflux ratio (1 part of outflow, 5 parts are returned in the still) steam 36gDFBN.After finishing, discharge vacuum with the sample filtering in the still and the water yield that exists with mensuration with the titration of Karl Fisher titrator (result all the time＜100ppm H
2O).In this solution, add internal standard substance (IPN, 6.42g) and DCBN (86g).The water yield of taking out sample in the still once more and existing (being set in order to prevent that sample from injecting that transfer pipet to be preheated to about 50 ℃ before taking a sample be important before the Karl Fisher titrator) with Karl Fisher titrator titration determination.This masterbatch is used in all quantitative screenings researchs that present embodiment describes.Be prepared as follows pipe.
Two cleaning stainless steel tubes that will have end cap are weighed separately and are tared after adding the 2.5-5mol% catalyzer.Then with the 5mL aliquots containig (about 5.5g) of the still liquid for preparing above with transfer pipet add in each pipe (for prevent to move on wall, solidify in the liquid process must be with solution and the preheating of heavy caliber transfer pipet).Pipe is covered and be screwed to about 40lbs with torque wrench and pincer pliers.With the pipe weigh once more and each the group in a pipe put into tubular reactor system together with the pipe (different catalyzer or blank) of 6 similar preparations.Pipe 200 ℃ of down heating 12 hours, is taken out then and replaces with second pipe in each group.Second group of pipe 220 ℃ of down heating 12 hours, cooled off then and take out.To manage the cooling and weigh to guarantee not take place seepage.Then open each pipe and add acetonitrile and make the material slurryization.Material is poured in 20mL pipe (shape) bottle, should be guaranteed that all materials are all poured out in treating processes from pipe.Make KF precipitation and aliquots containig is diluted in acetonitrile, then in the injection gas chromatography.Liquid chromatography is diluted and injected to another aliquots containig in the acetonitrile solution of 40wt%.With response factor information the component of product mixture is carried out quantitative analysis then.D part: catalyst test
Hat (ether) compound
* catalyzer time-temperature % transformation efficiency wt%DFBN wt%CFBN
180 ℃ 76.16 36.54 28.57 of dibenzo 12 hours
200 ℃ 90.49 40.31 31.21 of 18-C-6 12 hours
12 hours 220 ℃ 98.07 54.19 24.93
180 ℃ 56.58 34.79 13.75 of 12-C-4 12 hours
12 hours 200 ℃ 77.57 36.25 26.47
12 hours 220 ℃ 72.02 33.87 24.68
180 ℃ 87.99 40.14 31.22 of 15-C-5 12 hours
12 hours 200 ℃ 94.52 42.19 28.76
180 ℃ 89.51 39.17 30.00 of 12 hours 220 ℃ of 95.85 44.93 28.15 bicyclohexane and 18-C-6 12 hours
12 hours 200 ℃ 97.60 48.62 23.79
12 hours 220 ℃ 98.89 54.07 20.79
180 ℃ 89.45 50.03 37.32 of 18-C-6 12 hours
12 hours 200 ℃ 97.75 55.29 27.07
220 ℃ of 99.90 52.23 18.60* represented respectively in 12 hours :-dibenzo 18-C-6=dibenzo (B, K) (1,4,7,10,13,16) hexaoxacyclooctadecin:6,7,9,10,17,18,20,21-octahydro;-12-C-4=1,4,7,10-four oxa-cyclododecanes;-15-C-5=1,4,7,10,13-five oxa-cyclopentadecanes;-bicyclohexane also-18-C-6=2,5,8,15,18,21-six oxatricyclos (20.4.0.09,14) hexacosane;-18-C-6=1,4,7,10,13, the 16-hexaoxacyclooctadecane-6.
Ammonium salt
* catalyzer time-temperature % transformation efficiency wt%DFBN wt%CFBN
Ph (CH
3)
3180 ℃ 51.43 33.88 13.89 of NCl 12 hours
12 hours 200 ℃ 77.10 35.26 27.54
12 hours 220 ℃ 85.11 35.55 28.15
(C
5H
11)
4180 ℃ 69.39 32.22 24.20 of NBr 12 hours
12 hours 200 ℃ 80.16 38.43 28.32
12 hours 220 ℃ 85.72 39.62 32.19
Aliquat 336
*12 hours 180 ℃ 88.22 35.58 32.17
12 hours 200 ℃ 89.03 34.54 30.86
12 hours 220 ℃ 92.04 36.07 30.11
(C
12H
25) Me
3180 ℃ 92.26 43.97 31.70 of NBr 12 hours
12 hours 200 ℃ 94.68 45.30 26.95
12 hours 220 ℃ of 94.47 47.92 27.28CH
3(CH
2)
13N (CH
3)
3180 ℃ 91.02 37.62 32.11 of Br 12 hours
12 hours 200 ℃ 91.44 38.35 26.36
12 hours 220 ℃ 94.33 28.89 48.06
16,/60 12 hour 180 ℃ of 68.37 21.82 26.96 (C of ARQUAD
16H
33) N (CH
3)
3200 ℃ 75.19 17.17 26.42 of Br 12 hours
220 ℃ of 73.67 18.79 26.52* represented respectively in 12 hours: the hot ammonium of-phenyl trimethyl ammonium chloride-four pentyl brometo de amonio-Aliquat 336=1-: N-methyl-N, N-dioctyl (dioctil) muriate or tri-n-octyl methyl ammonium chloride;-Trimethyllaurylammonium bromide;-Tetradecyl Trimethyl Ammonium Bromide;-Arquad 16/60=cetyl trimethylammonium bromide.
12 hours 180 ℃ of 40.02 32.03 1.73Ph of phosphonium salt * catalyzer time-temperature % transformation efficiency wt%DFBN wt%CFBN (1-naphthyl methyl)
3200 ℃ 47.15 29.33 5.05 of PC 12 hours
12 hours 220 ℃ of 58.60 29.79 16.37 (methoxymethyies)
12 hours 180 ℃ of 42.55 28.28 1.33Ph
312 hours 180 ℃ of 39.63 31.65 1.97Ph of 12 hours 200 ℃ of 51.25 33.27 12.06 (3-nitrobenzyls) of PCl
3200 ℃ 46.68 34.95 5.35 of PBr 12 hours
12 hours 220 ℃ of 56.95 25.20 11.29Ph
4180 ℃ 47.69 26.14 5.77 of PCl 12 hours
12 hours 200 ℃ 56.75 26.86 11.57
220 ℃ of 64.96 27.04 19.92* represented respectively in 12 hours :-1-naphthyl methyl triphenyl phosphonium chloride;-methoxymethyl triphenyl phosphonium chloride;-3-nitrobenzyl three phenyl phosphonium bromides;-tetraphenyl phosphonium chloride.
The line style polyethers
Catalyzer time-temperature % transformation efficiency wt%DFBN wt%CFBN
180 ℃ 63.64 28.02 23.94 of IGEPAL CO-990 12 hours
12 hours 200 ℃ 80.58 33.20 31.07
12 hours 220 ℃ 93.52 43.81 31.54
180 ℃ 39.97 33.85 02.51 of BRIJ 30 12 hours
12 hours 200 ℃ 50.49 32.96 10.74
12 hours 220 ℃ 61.80 30.87 18.93
180 ℃ 40.34 34.54 02.60 of IGEPAL CA 520 12 hours
12 hours 200 ℃ 59.84 34.36 16.15
12 hours 220 ℃ 57.12 34.18 14.31
180 ℃ 41.71 32.64 04.84 of HEPTA EG MDE 12 hours
12 hours 200 ℃ 49.41 32.66 10.11
12 hours 220 ℃ 59.10 31.68 17.96
180 ℃ 40.46 33.90 04.30 of TRITON X-114 12 hours
12 hours 200 ℃ 49.66 33.60 11.26
12 hours 220 ℃ 63.77 33.33 23.21
180 ℃ 47.85 34.07 07.77 of NONA EG MDE 12 hours
12 hours 200 ℃ 47.26 32.93 08.06
12 hours 220 ℃ 69.77 31.54 24.27
180 ℃ 38.04 35.90 0 of IGEPAL CA 210 12 hours
12 hours 200 ℃ 64.76 53.82 06.48
12 hours 220 ℃ 37.66 31.76 09.55
180 ℃ 57.41 29.36 18.10 of IGEPAL CA 720 12 hours
12 hours 200 ℃ 74.50 32.48 27.91
12 hours 220 ℃ 83.93 34.74 31.48
180 ℃ 43.34 33.47 05.00 of POLYGLY-4000 12 hours
12 hours 200 ℃ 53.78 33.58 12.59
12 hours 220 ℃ 69.13 35.09 23.88
180 ℃ 53.85 32.63 12.84 of POLYGLY-E 3350 NF 12 hours
12 hours 200 ℃ 73.24 33.10 24.47
12 hours 220 ℃ 89.51 38.89 30.35
180 ℃ 40.46 33.90 04.30 of TRITON X-114 12 hours
12 hours 200 ℃ 49.68 33.60 11.28
180 ℃ 40 26 33.25 02.31 of 12 hours 220 ℃ of 63.77 33.33 23.21TETRA EG D1-P-Tocylate 12 hours
12 hours 200 ℃ 46.82 27.81 06.92
12 hours 220 ℃ 49.45 30.11 06.52
180 ℃ 44.88 34.71 04.76 of TETRA EG DME 12 hours
12 hours 200 ℃ 60.53 23.85 18.99
12 hours 220 ℃ 74.20 18.93 23.52
180 ℃ 39.36 31.17 04.40 of NONA EG DME 12 hours
12 hours 200 ℃ 61.14 31.01 19.15
12 hours 220 ℃ 64.91 30.24 23 45
180 ℃ 85.56 34.40 15.55 of POLYGLY-E 4500 NF 12 hours
12 hours 200 ℃ 81.30 39.04 30.40
180 ℃ 69.88 28.08 25.50 of 12 hours 220 ℃ of 93.84 46.00 31.31TETRA EG-BIS (9-Chinetyl) E 12 hours
12 hours 200 ℃ 82.90 25,080 29.91
220 ℃ of 94.80 36.20 27.08* represented respectively in 12 hours :-Igepal Co-990=(Nonylphenoxy polyethylene oxide);-Brij30=gathers (Oxy-1,2-ethane two bases), α-dodecyl, and ω-hydroxyl-;-Igepal CA 520=gathers (Oxy-1,2-ethane two bases), α-[(1,1,3, the 3-tetramethylbutyl) phenyl], ω-hydroxyl-(molecular-weight average=520);-seven glycol-monododecyl ether;-Triton X-114=polyoxyethylene glycol E-350,4-(1,1,3, the 3-tetramethyl butyl) phenyl ether;-nine glycol monododecyl ethers;-Igepal CA210;-Igepal CA 720=is identical with Igepal CA 520, but molecular-weight average is higher;-polyoxyethylene glycol-molecular-weight average 4000;-polyoxyethylene glycol-molecular-weight average 3500, nonfood grade; On-Triton X-114=sees; Two pairs-tosylate of-Tetraglycol 99;-tetraethylene glycol dimethyl ether;-nine glymes;-polyoxyethylene glycol-molecular-weight average 4500, nonfood grade; Two (8-chinonyl) ethers of-Tetraglycol 99.NF-nonfood grade EG-ethylene glycol DME-dme Ph-phenyl Me-methyl embodiment 9: reclaim dibenzo-18-and be preced with-6 crown ether catalyzer, reclaiming benzonitrile compound with stripping (vapor distillation) is solvent with methyl alcohol also
Obtain the sample of 195g real reaction product mixture.By three halogenide permutoid reactions the circulate DB-18 in this mixture, CFBN and the tar that part transforms.Following table provides the analysis and the weight of this reaction mixture.
Be used for the real reaction mixture that DB-18 reclaims
Component WT% (LC analysis) gram
DFBN 28.4 55.3
CFBN 46.6 90.9
DCBN 14.2 27.7
Internal standard substance 3.0 5.9
DB-18 3.1 6.0
Tar 4.7 9.2 is the LC=liquid chromatography wherein.
Stripping 161g benzonitrile from reaction product mixture stays dark fluid oil in very transparent water bottom.The steam stripped organism of 28.6g (bottom organic phase) decantation is gone into to be equipped with in the flask of 250g methyl alcohol.Under 20 ℃, stirred extraction tar 3 hours by magnetic stirrer.Catalyzer is filtered mutually, with about 10g methanol wash after drying.From filtrate, steam methyl alcohol and rinsing.The heavy 5.1g of the catalyzer that reclaims, its content is 98.2wt% by analysis.The heavy 23g of dried filtrate residue contains the 4.3wt%DB-18 that has an appointment.The catalyst recovery yield of estimating by filter cake and filtrate calculating is about 83wt%.The quality of the catalyzer that reclaims is identified (seeing embodiment 7) by using in the halogenide permutoid reaction of back.Identical when finding its active and yield basically with the use raw catalyst.Embodiment 10: reclaim dibenzo-18-with the vacuum distilling benzonitrile compound and be preced with-6 crown ether catalyzer in the Distallation systm that comprises a post
The synthetic mixture of the pure dibenzo of 15g-18-hat-6 crown ether catalyzer (available from Aldrich Chemicaland) and 41.4g tar (fluoridizing and the chlorination diaryl ether) is added in the mixture of 80g DFBN and CFBN.This mixture is added in the three neck round-bottomed flasks of the distiller (the vacuum jacket layer 10-tower tray Oldershaw post of jacket layer splitter and overhead product collection device is housed) that overhead stirrer and jacket layer are housed.Pressure is reduced to about 5mmHg absolute pressure and steam benzonitrile under heating.In experimentation, clearly owing to the delay of post, a certain amount of benzonitrile can flow back in the distilling flask when discharging vacuum.For attempting to reduce as far as possible quantity of reflux, nitrogen is blown into nation helps the cleaning post in the distilling flask.When reaching about 230 ℃, the still temperature can think that most of benzonitrile steams.5 to the 10g benzonitriles of estimating to have an appointment flow back in the still.To distill substrate (about 54g) and be cooled to about 120 ℃, be transferred to then in the 350g solvent that comprises 96wt% methyl alcohol, 3wt% acetone and 1wt% water.With this slurry stir about 2 hours, filter then, with 50g methanol wash after drying.Equally filtrate is evaporated to drying.The heavy 30.1g of gained dry cake, it contains the 60.2wt% catalyzer by analysis.Filtrate weighs 20.2g and contains the catalyzer of 3.7wt%, and the rate of recovery of estimated catalyst is 96wt%.The low-purity of catalyzer may be owing to used tar in this experiment causes.The content of wash-out tar that liquid-phase chromatographic analysis shows the back tar content that expection produces during apparently higher than DFBN produced according to the present invention.The elutriant of these back is the tripolymer of diaryl ether and the tetramer (promptly more high-molecular weight tar).These solvabilities of expecting when more high-molecular weight tar is with DFBN produced according to the present invention that the tar of generation is compared in methyl alcohol are tending towards lower.
It is believed that concentrating the pollution of tar when high temperature can cause and form some more high-molecular weight tar.Therefore, airtight Distallation systm is preferred when amplifying this recovery method in proportion.Also need trap be installed at the bottom of the distillation column to collect the benzonitrile stagnant liquid in the post or it is flowed in another container.This can prevent that benzonitrile from unnecessarily losing tar and removing in the stream.
Certainly, should understand the changes and improvements that can carry out (comprising the various catalyzer that use among the embodiment) wide region to above-mentioned embodiment preferred.Method of the present invention is not limited to the foregoing description, but comprises the content that can be explained by the instruction of describing in detail in the scope here.Therefore, the description of front is considered to illustrative and not restrictive, and should understand and intend limiting scope of the present invention with following claim (comprising all equivalents).
Claims (47)
1. produce 2 for one kind, the method for 6-difluoro benzonitrile comprises 2,6-dichloro-benzonitrile and anhydrous basically metal fluoride temperature about 160 ℃ to about 300 ℃ down with in the presence of the phase-transfer catalyst but in the presence of solvent-free, react.
2. the process of claim 1 wherein that phase-transfer catalyst is selected from polyethers, four Qu Dai phosphonium salts, four substituted ammonium salts and cryptand.
3. the process of claim 1 wherein to be reflected under about environmental stress and carry out.
4. the process of claim 1 wherein that temperature of reaction is about 190 ℃ to about 260 ℃.
5. the method for claim 4, wherein temperature of reaction is about 225 ℃.
6. the method for claim 2, wherein the polyethers catalyzer is crown ether or linear polyether.
7. the method for claim 6, wherein the crown ether catalyzer is selected from 18-hat-6 crown ethers, 15-hat-5 crown ethers, dibenzo-18-hat-6 crown ethers and bicyclohexane and 18-hat-6 ethers.
8. the side of claim 2 washes wherein that ammonium salt is selected from the phenyl trimethyl ammonium chloride, tetraphenylphosphonibromide bromide ammonium, tri-n-octyl methyl ammonium chloride, Trimethyllaurylammonium bromide, Tetradecyl Trimethyl Ammonium Bromide or cetyl trimethylammonium bromide.
9. the method for claim 2, Qi Zhong phosphonium salt is selected from 1-menaphthyl triphenyl phosphonium chloride, methoxymethyl triphenyl phosphonium chloride, 3-nitrobenzyl triphenyl phosphonium chloride and tetraphenyl phosphonium chloride.
10. the process of claim 1 wherein that metal fluoride is selected from Sodium Fluoride, cesium fluoride, Potassium monofluoride, rubidium fluoride and cuprous fluoride.
11. the process of claim 1 wherein that metal fluoride is selected from Potassium monofluoride.
12. produce 2 for one kind, the method for 6-difluoro benzonitrile comprises
A) 2,6-dichloro-benzonitrile and anhydrous alkaline metal fluoride cpd basically comprise 2-chlorine 6-fluorine benzonitrile, 2 down and in reaction generation in the presence of the phase-transfer catalyst but in the presence of solvent-free for about 160 ℃ to about 300 ℃ in temperature in reactor, 6-difluoro benzonitrile, unreacted 2, first kind of mixture of the tar that produces in 6-dichloro-benzonitrile, catalyzer and the reaction;
B) separate 2 from first kind of mixture, 6-difluoro benzonitrile generates and to comprise 2-chloro-6-fluorine benzonitrile, unreacted 2, second kind of mixture of the tar that produces in 6-dichloro-benzonitrile, catalyzer and the reaction; With
C) second kind of mixture is recycled in the reactor.
13. the method for claim 12 wherein is reflected under about environmental stress and carries out.
14. the method for claim 12, wherein temperature of reaction is about 190 ℃ to about 260 ℃.
15. the method for claim 14, wherein temperature of reaction is about 225 ℃.
16. the method for claim 12, wherein phase-transfer catalyst is selected from polyethers, four Qu Dai phosphonium salts, four substituted ammonium salts and cryptand.
17. the method for claim 12, wherein the polyethers catalyzer is crown ether or linear polyether.
18. the method for claim 17, wherein the crown ether catalyzer is selected from 18-hat-6 crown ethers, 15-hat-5 crown ethers, dibenzo-18-hat-6 crown ethers and bicyclohexane and 18-hat-6 ethers.
19. the method for claim 12, wherein ammonium salt is selected from the phenyl trimethyl ammonium chloride, tetraphenylphosphonibromide bromide ammonium, tri-n-octyl methyl ammonium chloride, Trimethyllaurylammonium bromide, Tetradecyl Trimethyl Ammonium Bromide or cetyl trimethylammonium bromide.
20. the method for claim 12, Qi Zhong phosphonium salt is selected from 1-menaphthyl triphenyl phosphonium chloride, methoxymethyl triphenyl phosphonium chloride, 3-nitrobenzyl triphenyl phosphonium chloride and tetraphenyl phosphonium chloride.
21. the method for claim 12, wherein metal fluoride is selected from Sodium Fluoride, cesium fluoride, Potassium monofluoride, rubidium fluoride and cuprous fluoride.
22. the method for claim 12, wherein metal fluoride is selected from Potassium monofluoride.
23. produce 2 for one kind, the method for 6-difluoro benzonitrile comprises
A) 2,6-dichloro-benzonitrile and anhydrous alkaline metal fluoride cpd basically comprise 2-chloro-6-fluorine benzonitrile, 2 down and in reaction generation in the presence of the phase-transfer catalyst but in the presence of solvent-free for about 160 ℃ to about 300 ℃ in temperature in reactor, 6 difluoro benzonitriles, unreacted 2, first kind of mixture of the tar that produces in 6-dichloro-benzonitrile, catalyzer and the reaction;
B) separate 2 from first kind of mixture, 6-difluoro benzonitrile generates and comprises 2-chloro-6-fluorine benzonitrile, 2, second kind of mixture of 6-dichloro-benzonitrile, tar and catalyzer;
C) separate 2 from second kind of mixture, 6-dichloro-benzonitrile and 2-chloro-6-fluorine benzonitrile generate the third mixture of comprising tar and catalyzer and with isolated 2,6-dichloro-benzonitrile and 2-chloro-6-fluorine benzonitrile are recycled in the reactor.
24. the method for claim 23 wherein is reflected under about environmental stress and carries out.
25. the method for claim 23, wherein temperature of reaction is about 190 ℃ to about 260 ℃.
26. the method for claim 25, wherein temperature of reaction is about 225 ℃.
27. the method for claim 23, wherein phase-transfer catalyst is selected from polyethers, four Qu Dai phosphonium salts, four substituted ammonium salts and cryptand.
28. the method for claim 27, wherein the polyethers catalyzer is crown ether or linear polyether.
29. the method for claim 28, wherein the crown ether catalyzer is selected from 18-hat-6 crown ethers, 15-hat-5 crown ethers, dibenzo-18-hat-6 crown ethers and bicyclohexane and 18-hat-6 ethers.
30. the method for claim 27, wherein ammonium salt is selected from the phenyl trimethyl ammonium chloride, tetraphenylphosphonibromide bromide ammonium, tri-n-octyl methyl ammonium chloride, Trimethyllaurylammonium bromide, Tetradecyl Trimethyl Ammonium Bromide or cetyl trimethylammonium bromide.
31. the method for claim 27, Qi Zhong phosphonium salt is selected from 1-menaphthyl triphenyl phosphonium chloride, methoxymethyl triphenyl phosphonium chloride, 3-nitrobenzyl triphenyl phosphonium chloride and tetraphenyl phosphonium chloride.
32. the method for claim 23, wherein metal fluoride is selected from Sodium Fluoride, cesium fluoride, Potassium monofluoride, rubidium fluoride and cuprous fluoride.
33. the method for claim 23, wherein metal fluoride is selected from Potassium monofluoride.
34. the method for claim 23 further comprises with the solvent that is selected from methyl alcohol, acetone, acetonitrile, toluene and chlorobenzene extracting tar from the third mixture.
35. the method for claim 34 also is included in extraction and reclaims catalyzer behind the tar.
36. the method for claim 35 also comprises the catalyst recirculation that reclaims is gone in the reactor.
37. produce 2 for one kind, the method for 6-difluoro benzonitrile comprises
A) be not higher than under about 130 ℃ in temperature in reactor that preparation comprises crown ether or linear polyether, 2 in the presence of solvent-free, the 6-dichloro-benzonitrile, anhydrous metal fluoride and one or more are selected from 2-chloro-6-fluorine benzonitrile and 2, first kind of mixture of the benzonitrile compound of 6-difluoro benzonitrile basically;
B) distill out be present in first kind of mixture up to the DFBN of about 75wt% and/or CFBN compound with dry first kind of mixture, generate second kind of mixture thus;
C) temperature of second kind of mixture is risen to about 160 to about 300 ℃ and comprise 2,6-difluoro benzonitrile, 2-chloro-6-fluorine benzonitrile, 2, the tar that produces in 6-dichloro-benzonitrile, the reaction and the third mixture of catalyzer with production;
D) separate 2 from the third mixture, 6-difluoro benzonitrile generates and comprises 2-chloro-6-fluorine benzonitrile, 2, the 4th kind of mixture of 6-dichloro-benzonitrile, tar and catalyzer.
38. the method for claim 37 wherein is reflected under about environmental stress and carries out.
39. the method for claim 37, wherein the temperature of step c) is about 190 ℃ to about 260 ℃.
40. the method for claim 39, wherein the temperature of step c) is about 225 ℃.
41. the method for claim 37, wherein the crown ether catalyzer is selected from 18-hat-6 crown ethers, 15-hat-5 crown ethers, 12-C-4 crown ether, dibenzo-18-hat-6 crown ethers and bicyclohexane and 18-hat-6 ethers.
42. the method for claim 37, wherein metal fluoride is selected from Sodium Fluoride, cesium fluoride, Potassium monofluoride, rubidium fluoride and cuprous fluoride.
43. the method for claim 37, wherein metal fluoride is selected from Potassium monofluoride.
44. the method for claim 37 further comprises from the 4th kind of mixture and separates 2,6-dichloro-benzonitrile and the production of 2-chloro-6-fluorine benzonitrile comprise the 5th kind of mixture of tar and catalyzer.
45. the method for claim 44 wherein extracts tar with the solvent that is selected from methyl alcohol, acetone, acetonitrile, toluene and chlorobenzene from the 5th kind of mixture.
46. the method for claim 45 is comprising reclaim catalyzer behind extraction tar.
47. the method for claim 46 is comprising the catalyst recirculation that reclaims is gone in the reactor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/365,726 US5502235A (en) | 1994-12-28 | 1994-12-28 | Solventless process for making 2,6 difluorobenzonitrile |
| US08/365,726 | 1994-12-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1174546A true CN1174546A (en) | 1998-02-25 |
Family
ID=23440092
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95197478A Pending CN1174546A (en) | 1994-12-28 | 1995-11-17 | Solventless process for making 2, 6 -difluorobenzonitrile |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5502235A (en) |
| EP (1) | EP0800506B1 (en) |
| JP (1) | JPH10511941A (en) |
| CN (1) | CN1174546A (en) |
| AR (1) | AR000556A1 (en) |
| AT (1) | ATE187959T1 (en) |
| AU (1) | AU702641B2 (en) |
| BR (1) | BR9510428A (en) |
| CA (1) | CA2209141A1 (en) |
| DE (1) | DE69514122T2 (en) |
| DK (1) | DK0800506T3 (en) |
| ES (1) | ES2139951T3 (en) |
| FI (1) | FI972742A (en) |
| HU (1) | HU215936B (en) |
| IL (1) | IL116634A (en) |
| TW (1) | TW307748B (en) |
| WO (1) | WO1996020168A1 (en) |
| ZA (1) | ZA9510902B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044388A (en) * | 2011-10-17 | 2013-04-17 | 张家港市国泰华荣化工新材料有限公司 | Preparation method of 3,4-difluoro sulfolane |
| CN112939782A (en) * | 2019-12-11 | 2021-06-11 | 浙江华晶氟化学科技有限公司 | Preparation method of fluorine-containing aryl compound |
| CN113024414A (en) * | 2021-03-23 | 2021-06-25 | 江苏合泰新材料科技有限公司 | Method for efficiently synthesizing fluorine-containing compound |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0847977B1 (en) * | 1995-06-20 | 2001-08-29 | Nippon Soda Co., Ltd. | 2,3-dihalogeno-6-trifluoromethylbenzene derivatives and process for producing the same |
| DE19702282C2 (en) * | 1997-01-23 | 1998-11-19 | Hoechst Ag | Catalyst for Halex reactions |
| AU2002304483A1 (en) * | 2001-05-17 | 2002-11-25 | Rhodia Chimie | Use of a composition of an ionic nature as a substrate reagent, a composition constituting a fluorination reagent and a method using same |
| DE10227223A1 (en) * | 2002-06-18 | 2004-01-08 | Kühlein, Klaus, Prof.Dr. | Process for the preparation of substituted organic compounds and use of catalysts for substitution reactions |
| CN104387289B (en) * | 2014-10-30 | 2017-09-01 | 天津河清化学工业有限公司 | The method of catalyst amount is reduced in difluorobenzonilyile production |
Family Cites Families (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB995927A (en) * | 1962-10-23 | 1965-06-23 | Imp Smelting Corp Ltd | Fluorination of perhalo compounds |
| NL302228A (en) * | 1962-12-20 | |||
| NL129620C (en) * | 1963-04-01 | |||
| US4051168A (en) * | 1976-05-12 | 1977-09-27 | E. I. Du Pont De Nemours And Company | Fluorination process |
| US4229365A (en) * | 1977-05-28 | 1980-10-21 | Basf Aktiengesellschaft | Manufacture of substituted fluorobenzenes |
| DE2803259A1 (en) * | 1978-01-26 | 1979-08-02 | Basf Ag | PROCESS FOR THE PRODUCTION OF FLUOROBENZENE |
| DE2902877C2 (en) * | 1978-01-28 | 1983-05-05 | I.S.C. Chemicals Ltd., London | Process for the preparation of a fluorobenzomononitrile |
| DE2938939A1 (en) * | 1978-10-05 | 1980-04-17 | Boots Co Ltd | METHOD FOR PRODUCING FLUORNITROBENZENE |
| US4174349A (en) * | 1978-10-30 | 1979-11-13 | Allied Chemical Corporation | Preparation of fluoroorganic compounds with calcium fluoride |
| FR2490634A1 (en) * | 1980-09-25 | 1982-03-26 | Rhone Poulenc Ind | PROCESS FOR THE PREPARATION OF FLUOROBENZONITRILES |
| JPS57197226A (en) * | 1981-05-30 | 1982-12-03 | Dainippon Ink & Chem Inc | Preparation of aromatic fluorine compound |
| EP0073372B1 (en) * | 1981-08-31 | 1984-08-01 | Ishihara Sangyo Kaisha, Ltd. | Process for producing 2,6-difluorobenzonitrile |
| EP0120575B1 (en) * | 1983-02-18 | 1989-06-14 | Nippon Shokubai Kagaku Kogyo Co., Ltd | Organic fluorine compounds |
| JPS604159A (en) * | 1983-06-23 | 1985-01-10 | Ishihara Sangyo Kaisha Ltd | Production of fluorobenzonitrile compound |
| US4704483A (en) * | 1984-04-27 | 1987-11-03 | Occidental Chemical Corporation | 3,4-difluoro-5-nitrobenzotrifluoride and preparation of fluoro-nitro-benzotrifluorides |
| US4952719A (en) * | 1984-10-15 | 1990-08-28 | Occidental Chemical Corporation | Process for the preparation of halo aromatic compounds |
| GB8500180D0 (en) * | 1985-01-04 | 1985-02-13 | Ici Plc | Chemical process |
| US4680406A (en) * | 1985-10-15 | 1987-07-14 | The Dow Chemical Company | Process for fluorinating halogenated organo-compounds |
| JPS62114939A (en) * | 1985-11-14 | 1987-05-26 | Sumitomo Chem Co Ltd | Production of fluorobenzene derivative |
| WO1987004149A1 (en) * | 1986-01-06 | 1987-07-16 | Mallinckrodt, Inc. | Phase transfer catalysts |
| WO1987004148A1 (en) * | 1986-01-06 | 1987-07-16 | Mallinckrodt, Inc. | Catalytic method for producing fluoroaromatic compounds using branched alkyl pyridinium salts |
| US4849552A (en) * | 1986-01-06 | 1989-07-18 | Mallinckrodt, Inc. | Preparation of fluoroaromatic compounds in dispersion of potassium fluoride |
| US4642398A (en) * | 1986-01-06 | 1987-02-10 | Mallinckrodt, Inc. | Preparation of fluoronitrobenzene compounds in dispersion of potassium fluoride |
| DE3642326A1 (en) * | 1986-12-11 | 1988-06-23 | Bayer Ag | METHOD FOR OBTAINING SUBSTITUTED FLUORBENZENE |
| US4973772A (en) * | 1987-02-07 | 1990-11-27 | Mallinckrodt, Inc. | Catalytic method for producing fluoroarmatic compounds using substituted pyridinium salts |
| JP2577567B2 (en) * | 1987-07-07 | 1997-02-05 | イハラケミカル工業株式会社 | Method for producing aromatic fluorine compound |
| DE3827436A1 (en) * | 1988-08-12 | 1990-02-15 | Bayer Ag | METHOD FOR IMPLEMENTING FLUORATOMES ON AROMATIC CORES BY NUCLEOPHILES EXCHANGE |
| WO1992000270A1 (en) * | 1990-06-25 | 1992-01-09 | Hoechst Aktiengesellschaft | Process for producing chlorofluoronitro benzenes and difluoronitro benzenes |
| EP0635486B1 (en) * | 1993-07-21 | 1998-12-09 | Clariant GmbH | Process for the preparation of fluorobenzonitriles |
-
1994
- 1994-12-28 US US08/365,726 patent/US5502235A/en not_active Expired - Fee Related
-
1995
- 1995-11-17 EP EP95940030A patent/EP0800506B1/en not_active Expired - Lifetime
- 1995-11-17 DE DE69514122T patent/DE69514122T2/en not_active Expired - Fee Related
- 1995-11-17 ES ES95940030T patent/ES2139951T3/en not_active Expired - Lifetime
- 1995-11-17 CA CA002209141A patent/CA2209141A1/en not_active Abandoned
- 1995-11-17 CN CN95197478A patent/CN1174546A/en active Pending
- 1995-11-17 JP JP8520445A patent/JPH10511941A/en not_active Ceased
- 1995-11-17 AT AT95940030T patent/ATE187959T1/en not_active IP Right Cessation
- 1995-11-17 DK DK95940030T patent/DK0800506T3/en active
- 1995-11-17 BR BR9510428A patent/BR9510428A/en not_active Application Discontinuation
- 1995-11-17 HU HU9701844A patent/HU215936B/en not_active IP Right Cessation
- 1995-11-17 WO PCT/US1995/014971 patent/WO1996020168A1/en active IP Right Grant
- 1995-11-17 AU AU41645/96A patent/AU702641B2/en not_active Ceased
- 1995-11-28 TW TW084112671A patent/TW307748B/zh active
- 1995-12-21 ZA ZA9510902A patent/ZA9510902B/en unknown
- 1995-12-27 AR ARP950100773A patent/AR000556A1/en unknown
- 1995-12-31 IL IL11663495A patent/IL116634A/en not_active IP Right Cessation
-
1997
- 1997-06-25 FI FI972742A patent/FI972742A/en unknown
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044388A (en) * | 2011-10-17 | 2013-04-17 | 张家港市国泰华荣化工新材料有限公司 | Preparation method of 3,4-difluoro sulfolane |
| CN103044388B (en) * | 2011-10-17 | 2015-04-15 | 张家港市国泰华荣化工新材料有限公司 | Preparation method of 3,4-difluoro sulfolane |
| CN112939782A (en) * | 2019-12-11 | 2021-06-11 | 浙江华晶氟化学科技有限公司 | Preparation method of fluorine-containing aryl compound |
| CN112939782B (en) * | 2019-12-11 | 2022-09-30 | 兰州康鹏威耳化工有限公司 | Preparation method of fluorine-containing aryl compound |
| CN113024414A (en) * | 2021-03-23 | 2021-06-25 | 江苏合泰新材料科技有限公司 | Method for efficiently synthesizing fluorine-containing compound |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1996020168A1 (en) | 1996-07-04 |
| HUT77239A (en) | 1998-03-02 |
| US5502235A (en) | 1996-03-26 |
| AR000556A1 (en) | 1997-07-10 |
| IL116634A0 (en) | 1996-03-31 |
| FI972742A0 (en) | 1997-06-25 |
| JPH10511941A (en) | 1998-11-17 |
| DE69514122T2 (en) | 2000-04-20 |
| AU4164596A (en) | 1996-07-19 |
| TW307748B (en) | 1997-06-11 |
| IL116634A (en) | 2003-04-10 |
| DE69514122D1 (en) | 2000-01-27 |
| ATE187959T1 (en) | 2000-01-15 |
| AU702641B2 (en) | 1999-02-25 |
| EP0800506A1 (en) | 1997-10-15 |
| HU215936B (en) | 1999-03-29 |
| BR9510428A (en) | 1998-07-07 |
| DK0800506T3 (en) | 2000-05-15 |
| EP0800506B1 (en) | 1999-12-22 |
| ES2139951T3 (en) | 2000-02-16 |
| FI972742A (en) | 1997-08-27 |
| ZA9510902B (en) | 1997-06-23 |
| CA2209141A1 (en) | 1996-07-04 |
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